Immunohistologic Analysis of Malignant Lymphoma 1. Accuracy of Histological Diagnosis and Usefulness of Monoclonal Antibodies

In order to test whether B cell or T cell origin of malignant lymphomas can be reliably suspected on histological basis alone, and to know the usefulness of some antibodies to lymphocytic cells which are currently available commercially, we reviewed 30 cases of malignant lymphomas both histologically and immunohistochemically. Hematoxylin- eosin stained sections from those cases were reclassified using Lukes and Collins\u27 classification with minor modification. Then, monoclonal antibodies; LCA, MT-1, and MB-1 have been applied to paraffin sections from same cases. In addition, four cases of plasmacytoma and a case of metastatic carcinoma which resembled malignant lymphoma were studied immunohistochemically. Our results indicate that (1) in most cases, T and B cell origin of lymphoma may be accurately classified by H-E stainecd section although further study with more cases is definitely necessary to reach this conclusion. (2) LCA immunoreactivity seemed to be stronger in lymphomas of T cell system. (3) MT-1 and MB-1 immunoreactivity did not correlate perfectly with LCA positivity. And (4) MT-1 ant MB-1 provide useful tools to dictate markers for T and B cell lymphomas in routinely fixed and paraffin-embedded tissue

Lck inhibition attenuate lung fibrosis by suppressing Treg activity

Background Lymphocyte-specific protein tyrosine kinase (Lck) is a member of the Src family of tyrosine kinases. The significance of Lck inhibition in lung fibrosis has not yet been fully elucidated, even though lung fibrosis is commonly preceded by inflammation caused by infiltration of Tcells expressing Lck. In this study, we examined the effect of Lck inhibition in an experimental mouse model of lung fibrosis. We also evaluated the effect of Lck inhibition on the expression of TGF-β1, an inhibitory cytokine regulating the immune function, in regulatory T-cells (Tregs). Methods Lung fibrosis was induced in mice by intratracheal administration of bleomycin. A-770041, a Lck-specific inhibitor, was administrated daily by gavage. Tregs were isolated from the lung using a CD4+CD25+ Regulatory T-cell Isolation Kit. The expression of Tgfb on Tregs was examined by flow cytometry and quantitative polymerase chain reaction. The concentration of TGF-β in bronchoalveolar lavage fluid (BALF) and cell culture supernatant from Tregs was quantified by an enzyme-linked immunosorbent assay. Results A-770041 inhibited the phosphorylation of Lck in murine lymphocytes to the same degree as nintedanib. A-770041 attenuated lung fibrosis in bleomycin-treated mice and reduced the concentration of TGF-β in BALF. A flow-cytometry analysis showed that A-770041 reduced the number of Tregs producing TGF-β1 in the lung. In isolated Tregs, Lck inhibition by A-770041 decreased the Tgfb mRNA level as well as the concentration of TGF-β in the supernatant. Conclusions These results suggest that Lck inhibition attenuated lung fibrosis by suppressing TGF-β production in Tregs and support the role of Tregs in the pathogenesis of lung fibrosis

PESI-MS for Diagnostic Cytology

Objectives: Cytology and histology are 2 indispensable diagnostic tools for cancer diagnosis, which are rapidly increasing in importance with aging populations. We applied mass spectrometry (MS) as a rapid approach for swiftly acquiring nonmorphological information of interested cells. Conventional MS, which primarily rely on promoting ionization by pre-applying a matrix to cells, has the drawback of time-consuming both on data acquisition and analysis. As an emerging method, probe electrospray ionization-MS (PESI-MS) with a dedicated probe is capable to pierce sample and measure specimen in small amounts, either liquid or solid, without the requirement for sample pretreatment. Furthermore, PESI-MS is timesaving compared to the conventional MS. Herein, we investigated the capability of PESI-MS to characterize the cell types derived from the respiratory tract of human tissues. Study Design: PESI-MS analyses with DPiMS-2020 were performed on various type of cultured cells including 5 lung squamous cell carcinomas, 5 lung adenocarcinomas, 5 small-cell carcinomas, 4 malignant mesotheliomas, and 2 normal controls. Results: Several characteristic peaks were detected at around m/z 200 and 800 that were common in all samples. As expected, partial least squares-discriminant analysis of PESI-MS data distinguished the cancer cell types from normal control cells. Moreover, distinct clusters divided squamous cell carcinoma from adenocarcinoma. Conclusion: PESI-MS presented a promising potential as a novel diagnostic modality for swiftly acquiring specific cytological information

コンピュータ上でのドラッグ・リポジショニングにより同定したPLK阻害薬は肺線維化を抑制する

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with few effective therapeutic options. Recently, drug repositioning, which involves identifying novel therapeutic potentials for existing drugs, has been popularized as a new approach for the development of novel therapeutic reagents. However, this approach has not yet been fully utilized in the field of pulmonary fibrosis. Methods: The present study identified novel therapeutic options for pulmonary fibrosis using a systematic computational approach for drug repositioning based on integration of public gene expression signatures of drug and diseases (in silico screening approach). Results: Among the top compounds predicted to be therapeutic for IPF by the in silico approach, we selected BI2536, a polo-like kinase (PLK) 1/2 inhibitor, as a candidate for treating pulmonary fibrosis using an in silico analysis. However, BI2536 accelerated mortality and weight loss rate in an experimental mouse model of pulmonary fibrosis. Because immunofluorescence staining revealed that PLK1 expression was dominant in myofibroblasts while PLK2 expression was dominant in lung epithelial cells, we next focused on the anti-fibrotic effect of the selective PLK1 inhibitor GSK461364. Consequently, GSK461364 attenuated pulmonary fibrosis with acceptable mortality and weight loss in mice. Conclusions: These findings suggest that targeting PLK1 may be a novel therapeutic approach for pulmonary fibrosis by inhibiting lung fibroblast proliferation without affecting lung epithelial cells. In addition, while in silico screening is useful, it is essential to fully determine the biological activities of candidates by wet-lab validation studies

Mental health conditions in Korean atomic bomb survivors: a survey in Seoul

More than 60 years have elapsed since the atomic bombings to Hiroshima and Nagasaki, and since all of the atomic bomb survivors have become old, the importance of caring their mental health has become increasing in Japan. Although approximately 70% of overseas atomic bomb are living in Korea, there have been quite few studies on their mental health. The objectives of the present study were to elucidate whether the mental health conditions of atomic bomb survivor in Korea are similar to those in Japan. The subjects were 181 Korean atomic bomb survivors living in Korea (cases) and 209 outpatients of a hospital in Seoul who were not exposed to atomic bombs (controls). Interviewers administered them at the hospital a questionnaire with Impact of Event Scale-Revised, General Health Questionnaire 12 (GHQ-12), Korean version of short form Geriatric Depression Scale and the K scale of the Minnesota Multiphasic Personality Inventory. Excluding subjects with incomplete responses we analyzed 162 cases and 189 controls. The proportion of subjects with high score of GHQ-12 ( 4) was significantly higher in cases (78/162 or 48.1%) than in controls (42/189 or 22.2%) (p < 0.0001, Fisher\u27s exact test). The present results, though preliminary, indicate that atomic bomb survivors in Korea have also mental health problems similar to those observed in Japanese atomic bomb survivors, indicating the necessity of a larger study

A multi-ethnic meta-analysis identifies novel genes, including ACSL5, associated with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a devastating progressive motor neuron disease that affects people of all ethnicities. Approximately 90% of ALS cases are sporadic and thought to have multifactorial pathogenesis. To understand the genetics of sporadic ALS, we conducted a genome-wide association study using 1,173 sporadic ALS cases and 8,925 controls in a Japanese population. A combined meta-analysis of our Japanese cohort with individuals of European ancestry revealed a significant association at the ACSL5 locus (top SNP p = 2.97 × 10−8). We validated the association with ACSL5 in a replication study with a Chinese population and an independent Japanese population (1941 ALS cases, 3821 controls; top SNP p = 1.82 × 10−4). In the combined meta-analysis, the intronic ACSL5 SNP rs3736947 showed the strongest association (p = 7.81 × 10−11). Using a gene-based analysis of the full multi-ethnic dataset, we uncovered additional genes significantly associated with ALS: ERGIC1, RAPGEF5, FNBP1, and ATXN3. These results advance our understanding of the genetic basis of sporadic ALS

Stress-impaired reward pathway promotes distinct feeding behavior patterns

Although dietary behaviors are affected by neuropsychiatric disorders, various environmental conditions can have strong effects as well. We found that mice under multiple stresses, including social isolation, intermittent high-fat diet, and physical restraint, developed feeding behavior patterns characterized by a deviated bait approach (fixated feeding). All the tested stressors affected dopamine release at the nucleus accumbens (NAcc) shell and dopamine normalization reversed the feeding defects. Moreover, inhibition of dopaminergic activity in the ventral tegmental area that projects into the NAcc shell caused similar feeding pattern aberrations. Given that the deviations were not consistently accompanied by changes in the amount consumed or metabolic factors, the alterations in feeding behaviors likely reflect perturbations to a critical stress-associated pathway in the mesolimbic dopamine system. Thus, deviations in feeding behavior patterns that reflect reward system abnormalities can be sensitive biomarkers of psychosocial and physical stress